The origin of pharmacological effect of novel drug substances is their ability to interact with serotonin 5-HT6 receptors playing the key role in treatment of central nervous system diseases (CNS), in particular, Alzheimer's disease (AD), Huntington's disease, schizophrenia, other neurodegenerative diseases, cognitive disorders and obesity.
Usefulness of selective antagonists of serotonin 5-HT6 receptors for treating of CNS diseases, in particular, schizophrenia, AD and other neurodegenerative diseases and cognitive disorders was conclusively proved in preclinical investigation and is regarded to be very perspective in medicine of future. [Holenz J., Pauwels P. J., Diaz J. L., Merce R., Codony X., Buschmann H. Medicinal chemistry strategies to 5-HT6 receptor ligands as potential cognitive enhancers and antiobesity agents. Drug Disc. Today. 2006; 11:283-299]. At mammals these receptors are localized exclusively in central nervous system (CNS), and mainly in parts of brain responsible for training and memory. [Ge'rard C., Martres M.-P., Lefe'vre K., Miguel M.-C., Verge' D., Lanfumey L., Doucet E., Hamon M., El Mestikawy S. Immuno-localisation of serotonin 5-HT6 receptor-like material in the rat central nervous system. Brain Research. 1997; 746:207-219]. Besides, it was shown [Dawson L. A., Nguyen H. Q., Li P. The 5-HT(6) receptor antagonist SB-271046 selectively enhances excitatory neurotransmission in the rat frontal cortex and hippocampus. Neuropsychopharmacology. 2001; 25:662-668], that 5-HT6 receptors are modulators of the whole number of neuromediator systems including cholinergic, noradrenergic, glutamatergic and dopaminergic. Taking into account the fundamental role of these systems in normal cognitive processes and their dysfunction at neurodegeneration, exclusive role of 5-HT6 receptors in forming normal and “pathological” memory becomes obvious.
In a large number of nowadays publications it was shown that blocking of 5-HT6 receptors leads to considerable enhancement of memory consolidation in various animal models of training-memorizing-reproduction [Foley A. G., Murphy K. J., Hirst W. D., Gallagher H. C., Hagan J. J., Upton N., Walsh F. S., Regan C. M. The 5-HT(6) receptor antagonist SB-271046 reverses scopolamine-disrupted consolidation of a passive avoidance task and ameliorates spatial task deficits in aged rats. Neuropsychopharmacology. 2004; 29:93-100; Riemer C., Borroni E., Levet-Trafit B., Martin J. R., Poli S., Porter R. H., Bos M. Influence of the 5-HT6 receptor on acetylcholine release in the cortex: pharmacological characterization of 4-(2-bromo-6-pyrrolidin-1-ylpyridine-4-sulfonyl)phenylamine, a potent and selective 5-HT6 receptor antagonist. J. Med. Chem. 2003; 46:1273-1276; King M. V., Woolley M. L., Topham I. A., Sleight A. J., Marsden C. A., Fone K. C. 5-HT6 receptor antagonists reverse delay-dependent deficits in novel object discrimination by enhancing consolidation e an effect sensitive to NMDA receptor antagonism. Neuropharmacology 2004; 47:195-204]. It was also demonstrated that considerable enhancement of cognitive functions in aged rats took place under the action of 5-HT6 receptor antagonists in Morrison's water maze experiment [Foley A. G., Murphy K. J., Hirst W. D., Gallagher H. C., Hagan J. J., Upton N., Walsh F. S., Regan C. M. The 5-HT(6) receptor antagonist SB-271046 reverses scopolamine-disrupted consolidation of a passive avoidance task and ameliorates spatial task deficits in aged rats. Neuropsychopharmacology. 2004; 29:93-100]. Recently more thorough understanding of 5-HT6 receptor function in cognitive processes and more accurate conceptions concerning possible pharmacophoric properties of their antagonists were achieved. [Holenz J., Pauwels P. J., Diaz J. L., Merce R., Codony X., Buschmann H. Medicinal chemistry strategies to 5-HT6 receptor ligands as potential cognitive enhancers and antiobesity agents. Drug Disc. Today. 2006; 11:283-299]. This resulted in preparation of highly affine selective ligands (“molecular tools”), and later to clinical candidates. At present a number of 5-HT6 receptor antagonists are at various phases of clinical investigation as potential drug substances for treatment of AD, Huntington's disease, schizophrenia (antipsychotic) and other neurodegenerative and cognitive diseases (Table 1) [http://integrity.prous.com].
TABLE 15-HT6 Receptor antagonists as drug candidates.Clinical phase Medicamentof testingDeveloperTherapeutic groupDimebon ™Phase IIIMedivation (USA)Alzheimer's diseasetreatmentSGS-518Phase IILilly, SaegisCognitive diseasestreatmentSB-742457Phase IIGlaxoSmithKlineAlzheimer's diseasetreatment;AntipsychoticDimebon*Phase I/IIaMedivation (USA)Huntington's diseasetreatmentDimebon*Phase II(Russia)SchizophreniaPRX-07034Phase IEpix Pharm.Obesity treatment;Antipsychotic;Cognitive diseasestreatmentSB-737050APhase IIGlaxoSmithKlineAntipsychoticBVT-74316Phase IBiovitrumObesity treatmentSAM-315Phase IWyeth Pharm.Alzheimer's diseasetreatmentSYN-114Phase IRoche, Synosis Cognitive diseasesTher.treatmentBGC-20-761PreclinicalBTG (London)Antipsychotic;Cognitive diseasestreatmentFMPOPreclinicalLillyAntipsychoticDimebon ™Preclinical(Russia)Insult treatment
Another attractive property of 5-HT6 receptor antagonists is their ability to suppress appetite that can lead to the development on their basis of essentially novel remedies for overweight lowering and obesity treatment. [Vicker S. P., Dourish C. T. Serotonin receptor ligands and the treatment of obesity. Curr. Opin. Investig. Drugs. 2004; 5:377-388]. This effect was confirmed in many investigations [Holenz J., Pauwels P. J., Diaz J. L., Merce R., Codony X., Buschmann H. Medicinal chemistry strategies to 5-HT6 receptor ligands as potential cognitive enhancers and antiobesity agents. Drug Disc. Today. 2006; 11:283-299. Davies S. L. Drug discovery targets: 5-HT6 receptor. Drug Future. 2005; 30:479-495], its mechanism is based on suppression of γ-aminobutyric acid signaling by 5-HT6 receptor antagonists and increasing of α-melanocyte-stimulating hormone emission, that, finally, results in lowering of food demand [Woolley M. L. 5-ht6 receptors. Curr. Drug Targets CNS Neurol. Disord. 2004; 3:59-79]. Now two antagonists of 5-HT6 receptors are at the first phase of clinical testing as drug candidates for obesity treatment (Table 1) [http://integrity.prous.com].
In this context searching for new selective and effective serotonin 5-HT6 receptor antagonists seems to be original and perspective approach to the development of novel drug substances for treating of a great number of neurological and neurodegenerative diseases and cognitive disorders.
There are many publications in scientific literature concerning various biologically active sulfonyl substituted azaheterocycles, among them ligands of serotonin receptors. For example, substituted 1-(2-aminoethyl)-4-(arylsulfonyl)pyrazoles of general formula A1 were described as serotonin 5-HT2c receptor ligands [WO 2003057674 A1] and substituted 7-amino-3-(sulfonyl)pyrazolo[1,5-a]pyrimidines A2 as serotonin 5-HT6 receptor antagonists [EP 941994 A1, 1999]
A1: Ar=alkyl, aryl; R1 and R2=H, OH, alkyl, alkoxy; R3 and R4=H, alkyl, aryl.A2: Ar=aryl, heterocyclyl; R1=H, alkyl, alkylthio; R2=H, alkyl, halogen; R3=H, alkyl, hydroxyalkyl; R4 and R5=H; NR4R5=piperazinyl.
With the aim of working out novel highly effective neuroprotective medicaments the authors of the invention carried out widespread investigation in the field of substituted 3-(sulfonyl)pyrazolo[1,5-a]pyrimidines, as a result of which novel drug substances which were 5-HT6 receptor antagonists were found.